Podcast Summary: In this podcast, Linas Pupelis, Senior Product Manager at Thermo Fisher Scientific, discusses the latest development of critical raw materials required to support the synthesis of mRNA for therapeutic development. This includes review of our TheraPure reagents, specifically designed and carefully manufactured, following the principles of 21 CRF 210/211 and ICH Q7.
BIOPHARM: The two currently approved COVID-19 emergency use authorization (EUA) vaccines are based on mRNA technology. What are the challenges developing this entirely new drug class?
LINAS PUPELIS: Today, the biggest challenges can be grouped into two categories: technical challenges in the mRNA technology and challenges related to manufacturing. Regarding technical challenges, one of the greatest is mRNA stability. N nuclease enzyme degrade mRNA within minutes. To stabilize mRNA, researchers look for solutions to make mRNA transcript less attractive to nucleases. This challenge can be overcome by modifying 3-prime and 5-prime ends of mRNA to make it less attractive to nucleases.
Another technical challenge is how the human immune system frequently perceives foreign RNA as a threat. This problem can be resolved by using chemically modified nucleotides 5-methylcytosine or pseudouridine instead of cytosine and uracil nucleotides. Such substitutions can mute the immune response while also bolstering the stability of the mRNA and the efficiency of translation. Thermo Fisher offers a variety of such modified nucleotides as part of its therapeutic product family.
Finally, we have challenges related to manufacturing requirements. The main one is that it is critical that raw materials are safe for commercial use. To combat this, Thermo Fisher provides the highest purity and safety raw materials suitable for mRNA vaccine manufacturing.
BIOPHARM: What are the major requirements in raw materials used for mRNA therapeutic development?
PUPELIS: mRNA vaccines are for human use, thus the major requirements in raw materials are related to purity and safety. These properties are achieved by ensuring that raw materials are animal-origin free and beta-lactam free. This eliminates risks of transmissible diseases or viral agents, as well as risks of allergic reactions and other side effects. Raw material purity is insured through bioburden and endotoxin testing. Also, raw materials are managed through mature quality systems and extensive quality control testing. This ensures lot-to-lot consistency, which is important for smooth, raw material use.
BIOPHARM: How is Thermo Fisher working to address these quality requirements by therapeutic companies?
PUPELIS: At Thermo Fisher, we have launched the TheraPure product family. These therapeutic reagents are designed for pharmaceutical manufacturers who are looking for tools and core building blocks to use in research and manufacturing. These reagents are crafted in facilities with thoroughly documented quality systems that are audited by accredited registrars. And, these therapeutic products are strategically designed and carefully manufactured following their cGMP principles.
BIOPHARM: Are there major issues in mRNA manufacturing today for therapeutics customers?
PUPELIS: There are some major challenges, including raw materials quality and volume, especially with EUA approval of COVID-19 as an mRNA[-based] vaccine to be used effectively against the viral infection. Global demand for mRNA syntheses has grown. mRNA therapeutic developers, including those for COVID-19 vaccines, need immediate, adequate quality raw material suitable for the production of mRNA in a very large scale.
BIOPHARM: From a capacity standpoint, what is Thermo Fisher working on to address capacity issues?
PUPELIS: Historically, Thermo Fisher served academic and research labs, which did not require high-grade raw materials in large scales. Over the years, we saw growing potential in mRNA therapeutics. Thus, we have increased our ability to scale and designed single-use system manufacturing, which ensures the highest grade of raw materials.
In 2020, Thermo Fisher built a new facility in Vilnius, Lithuania, for industrial-scale manufacturing to ensure we can meet the demand required by vaccine manufacturers. Moreover, we are building manufacturing redundancies in several locations in the United States for reagents used in mRNA synthesis. This will ensure a stable supply and that our raw materials will be accessible from multiple sites on different continents.
BIOPHARM: What do you think the future of mRNA therapeutics and demand will be for raw material?
PUPELIS: We just saw multiple countries approve mRNA-based vaccines, so the future is bright. As one scientific journal wrote, COVID-19 actually unlocked a new category of vaccines. That development makes this moment in history significant.
First, this is a new technology. It is faster, easier, and cheaper to manufacture an mRNA vaccine compared to traditional vaccines. These benefits bring value to everyday people, and this breakthrough makes vaccines more accessible to people around the world.
At Thermo Fisher, we are working hard and are well-positioned to help customers find everything they need, including in-vitro transcription enzymes, nucleotides, mRNA modification tools, mRNA purification technologies, and solutions for vaccine delivery. As mRNA vaccine approval increases globally, this is the start of addressing many more diseases with mRNA technology.
For Research Use Only. Not for use in diagnostic procedures.